Abstract
The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies.
Highlights
Parkinson’s disease (PD) is a major neurodegenerative disease causing progressive motor disability in individuals over 55–60 years of age and affects both genders with a slight male preponderance [1,2,3]
Currently prevailing consensus maintains that PD is the result of chronical loss of dopaminergic neurons in substantia nigra-pars compacta (SNpc), which culminates with dysregulated modulatory innervations into the striatum and resultant dysfunction of the nigro-striatal-cortical circuitry in the basal ganglia [1,2,11]
Since the early discovery of α-syn as a major component of Lewy bodies (LBs) pathology in PD, and genetic linkage between mutations in the SNCA with rare forms of familial PD [30,240,241,242], significant progress has been made to make a compelling case for a pathogenic role of α-syn aggregation in PD and related diseases [12,17,240]
Summary
Parkinson’s disease (PD) is a major neurodegenerative disease causing progressive motor disability in individuals over 55–60 years of age and affects both genders with a slight male preponderance [1,2,3]. As in the case of intracerebral LRP in iLBD [164], it remains unsettled if these individuals eventually will progress to develop a Lewy body disorder or represent a population with an intact ENS function Based on these findings, a significant development in the field has been to investigate if α-syn misfolding and propagation in the nervous system occurs in a ‘prion-like’ fashion, i.e., templating of endogenous physiological α-syn into misfolded conformers formed in situ or received from a neuroanatomically connected location [23,165]. This implies that the neuroinflammatory processes are contributors to the disease, some recent reports indicate that activated microglia may be a source of neurotrophic factors and play a neuroprotective role (Figure 2) [180,212]
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